The treatment of locoregional relapses or second lung cancers in patients who have received prior radiation therapy to the thorax is a difficult clinical problem. These patients are rarely surgical candidates (4
), and traditional chemotherapy and radiation therapy approaches are generally unsuccessful in providing durable disease control (5
). As such, new therapies, and probably combinations of therapies, are required for more effective treatment in such cases. Previous studies have demonstrated the effectiveness of SBRT for managing early-stage NSCLC (13
). In this study, we present our early experience with SBRT for locoregional relapse or second cancers appearing after thoracic irradiation.
Consistent with previous reports of SBRT for early-stage NSCLC (15
), SBRT also provided a high rate in field local control in the group reported here. Interestingly, all three of the in-field failures occurred in the subset of patients undergoing reirradiation for in-field relapses. It is possible this reflects some form of radiation resistance, as has been described regarding reirradiation at other sites (21
). It is also possible that disruption of the tissue architecture in the previously treated field made SBRT targeting difficult. However, because only one of these three patients received what previous studies have demonstrated to be a sufficient biologically effective dose to the PTV, it is also possible that our findings reflect SBRT underdosing in these two cases. Larger studies would be required to determine the relative contributions of these possible factors.
Despite the high rate of in-field control, the rate of intrathoracic relapse seen in this study was considerable, with an estimated 2-year relapse rate of 74%. This high rate of intrathoracic relapse is consistent with previous reports (6
) and likely speaks to the underlying tumor biology in the patients being treated. The timing of these relapses suggests that these patients had harbored microscopic if not macroscopic disease at the time of SBRT. Consistent with this hypothesis was our finding of significantly better progression-free survival in the subset of patients who underwent SBRT for isolated recurrence (or second cancer) outside the previous treatment field. Taken together, these results suggest that it may be possible to identify patients for whom SBRT would be a good salvage therapy, and perhaps also patients who may benefit from SBRT in combination with systemic therapy.
The overall rates of SBRT-associated toxicity in this study were considerable and significantly higher than previously seen for patients with early SNCLC cancer treated with SBRT (15
). However, some of the worsening dyspnea, the most common side effect, may be part of the natural process of chronic obstructive pulmonary disease and radiation-induced pneumonitis from prior radiation therapy, as may also be the case for the chest wall pain. We found an interesting dichotomy in the toxicity profile: patients who were retreated for in-field relapses experienced higher rates of chest wall pain and lower rates of pneumonitis than did those given SBRT to targets outside the previous treatment field. Conversely, patients who were treated for lesions that lay outside the previous treatment field experienced higher rates of pneumonitis but lower rates of chest wall pain. The reason for this difference is not clear but may speak to differences in the biologic basis of these conditions. Radiation pneumonitis is believed to be an inflammatory process, and some have hypothesized that previously irradiated areas have already undergone fibrosis and are less susceptible to radiation-induced inflammation (7
). The underlying biology of SBRT-associated chest wall pain is not well understood (24
) but probably represents a mix of conditions including nerve damage, fractures, and myositis. Prior radiation and high cumulative doses would likely predispose individuals to any of these conditions. However, this hypothesis is based on the results gathered from a small number of patients; it is possible that these biologic considerations may prove less important when the relationship between these side effects and the anatomic location, dose, and volume of the treatment is understood. Another limitation of our study is the relatively short follow-up period, which precludes assessment of very late toxicity. Additional information on this endpoint will require continued contact with this initial cohort of SBRT patients.
Comparisons between this study of SBRT and other retrospective studies of conventional reirradiation for lung tumors are difficult for several reasons. First, these studies involved heterogeneous groups of patients treated with both definitive and palliative intent who presented with both symptomatic and asymptomatic disease (6
). Because all of the patients on our study were treated for radiographically identified disease and all were treated with definitive intent, our group may well represent a population with more favorable prognosis. Second, many of these studies seem to have only included lesions inside the prior radiation field (6
), whereas our study included both in-field and out-of-field relapses. Nevertheless, the excellent in-field control rate in our cohort as a whole (92%) and the 75% control rate in the subset of patients undergoing reirradiation for in-field relapses compare favorably to the response rates for patients given definitive treatment in the other reports (6
). As such, SBRT likely represents a substantial improvement over fractionated EBRT for those patients who would benefit from improved in field control.
The comparative cost of this high control rate in terms of toxicity is difficult to assess. Certainly, chest wall pain is a side affect of SBRT that is not associated with fractionated radiation therapy. With an incidence of 31%, this is a significant toxicity that must be considered when comparing these modalities for reirradiation. In contrast, both modalities are associated with a low rate of clinically significant esophagitis (<10%), and it is likely that the actual incidence of this side effect depends more on tumor location than the treatment modality used (6
). How the choice of treatment modality affects the rate of symptomatic pneumonitis is less clear. The 50% incidence of symptomatic pneumonitis seen in this study with SBRT-based reirradiation is significant. However, the rates of symptomatic pneumonitis after definitive fractionated reirradiation have been reported from 8% to 55% (6
). Because all these studies contain small numbers of patients with heterogeneous populations in terms of performance status and pretreatment lung function, a definitive comparison between these modalities is not possible.